This application is a U.S. National Phase application under 35 U.S.C. xc2xa7 371 of PCT Application No. PCT/GB00/00974, filed Mar. 16, 2000, which claims priority under 35 U.S.C. xc2xa7 119 from GB Application No. 9906480.0, filed Mar. 19, 1999 and GB Application No. 9924616.7 filed Oct. 18, 1999.
This invention relates to a class of tetrahydropyran compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1(NK-1) receptor antagonists.
The present invention provides compounds of the formula (I): 
wherein
R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
R3 is hydrogen, halogen or fluoroC1-6alkyl;
R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
R6 represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
R7 represents halogen, hydroxy, C2-4alkenyl, C2-4alkynyl, N3, xe2x80x94NR11R12, xe2x80x94NRaCORb, xe2x80x94OSO2Ra, xe2x80x94(CH2)pNRa(CH2)qCOORb, CORa, COORa, xe2x80x94Nxe2x95x90Cxe2x95x90O, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from xe2x95x90O, xe2x95x90S, halogen, hydroxy, xe2x80x94SH, CORa, CO2Ra, xe2x80x94ZNR11R12, C1-4alkyl, hydroxyC1-4alkyl, fluoroC1-4alkyl, chloroC1-4alkyl, C1-4alkoxy, fluoroC1-4alkoxy or C1-4alkoxy substituted by a C1-4alkoxy or hydroxyl group, and wherein said C2-4alkenyl and C2-4alkynyl groups are optionally substituted by a substituent selected from halogen, hydroxy, N3, xe2x80x94NR11R12, xe2x80x94NRaCORb, xe2x80x94OSO2Ra, xe2x80x94(CH2)pNRa(CH2)qCOORb, CORa or COORa;
R8 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, hydroxy, C1-6alkoxy or hydroxyC1-6alkyl;
R9 and R10 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORc, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, C1-6alkyl or phenyl;
R11 is hydrogen, C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group, or R11 is a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined;
R12 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group;
or R11, R12 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, CORe, CO2Re, C1-4alkyl optionally substituted by a C1-4alkoxy or hydroxyl group, or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, or a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined, or said heteroaliphatic ring is substituted by a spiro-fused lactone ring, and said heteroaliphatic ring optionally containing a double bond, which heteroaliphatic ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRd moiety, where Rd is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, and where Re is hydrogen, C1-4alkyl or benzyl;
or R11, R12 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or R11, R12 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S;
Z represents a bond, C1-6alkylene or C3-6cycloalkylene;
n is zero, 1 or 2;
p is 1 or 2; and
q is 1 or 2;
and pharmaceutically acceptable salts thereof.
A preferred class of compounds of formula (I) is that wherein:
R7 represents halogen, hydroxy, C2-4alkenyl, N3, xe2x80x94NR11R12, xe2x80x94NRaCORb, xe2x80x94OSO2Ra, xe2x80x94(CH2)pNRa(CH2)qCOORb, CORa, COORa, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from xe2x95x90O, xe2x95x90S, halogen, hydroxy, xe2x80x94SH, CORa, CO2Ra, xe2x80x94ZNR11R12, C1-4alkyl, hydroxyC1-4alkyl, fluoroC1-4alkyl, C1-4alkoxy, fluoroC1-4alkoxy or C1-4alkoxy substituted by a C1-4alkoxy or hydroxyl group.
Another preferred class of compounds of formula (I) is that wherein:
R7 represents halogen, hydroxy, C2-4alkenyl, N3, xe2x80x94NR11R12, xe2x80x94NRaCORb, xe2x80x94OSO2Ra, xe2x80x94(CH2)pNRa(CH2)qCOORb or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from xe2x95x90O, xe2x95x90S, halogen, hydroxy, xe2x80x94SH, CORa, CO2Ra, xe2x80x94ZNR11R12, C1-4alkyl, hydroxyC1-4alkyl, fluoroC1-4alkyl, C1-4alkoxy, fluoroC1-4alkoxy or C1-4alkoxy substituted by a C1-4alkoxy or hydroxyl group;
R11 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group;
R12 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by a C1-4alkoxy or hydroxyl group;
or R11, R12 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, CORa, CO2Ra or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and said ring optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRd moiety where Rd is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R11, R12 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or a pharmaceutically acceptable salt thereof.
A further preferred class of compounds of formula (I) is that wherein R1 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
Another preferred class of compounds of formula (I) is that wherein R2 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
Also preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
A particularly preferred class of compounds of formula (I) is that wherein R1 is fluorine, chlorine or CF3.
Another particularly preferred class of compounds of formula (I) is that wherein R2 is hydrogen, fluorine, chlorine or CF3.
Also particularly preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
Preferably R1 and R2 are in the 3 and 5 positions of the phenyl ring.
More preferably R1 is 3-fluoro or 3-CF3.
More preferably R2 is 5-fluoro or 5-CF3.
More preferably R3 is hydrogen.
Most preferably R1 is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.
A further preferred class of compound of formula (I) is that wherein R4 is hydrogen.
Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen and R5 is hydrogen or 4-fluoro.
R6 is preferably C1-4alkyl optionally substituted by hydroxy. In particular, R6 is preferably a methyl or hydroxymethyl group.
Where xe2x80x94NR11R12 is defined as a substituent R7 or as a substituent on a heteroaromatic ring in the definition of R7, then R11 may aptly be a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or C1-2alkoxy group, R12 may aptly be a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or C1-2alkoxy group, or R11 and R12 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxy or C1-2alkoxy group. Particularly preferred heteroaliphatic rings formed by xe2x80x94NR11R12 are azetidine, pyrolidine, piperidine, morpholine, piperazine and N-methylpiperazine, and especially piperidine.
Where the group NR11R12 represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by two groups, the first substituent, where present, is preferably selected from hydroxy, CO2Re (where Re is hydrogen, methyl, ethyl or benzyl), or C1-2alkyl substituted by hydroxy. Where present, the second substituent is preferably a methyl group. Where two substituents are present, said substituents are preferably attached to the same carbon atom of the heteroaliphatic ring.
Where the group NR11R12 represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by a spiro-fused lactone ring, a particularly preferred example is: 
Another preferred example is: 
Where the group NR11R12 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR11R12 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where the group NR11R12 represents a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, said heteroaromatic ring is preferably a five-membered ring, in particular a pyrrole, imidazole or triazole ring, a nitrogen atom of which is preferably included in the heteroaliphatic ring. Suitable examples of such fused ring systems include 
Particularly suitable moieties NR11R12 include those wherein NR11R12 is amino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino.
Where R7 represents an optionally substituted five or six-membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, the heteroaromatic ring is selected from pyrrole, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole.
Preferred compounds of the present invention are those wherein R7 is a group selected from imidazole, 1,2,3-triazole and 1,2,4-triazole.
Particularly preferred compounds of the present invention are those wherein R7 is a group selected from imidazol-1-yl and 1,2,4-triazol-1-yl.
Where R7 represents an optionally substituted five membered or six membered nitrogen-containing heteroaromatic ring, preferred substituents are xe2x80x94ZNR11R12 and C1-2alkyl (especially methyl). With reference to the group ZNR11R12 defined as a substituent on a heteroaromatic ring in the definition of R7, Z may be a bond or a linear, branched or cyclic group. Favourably Z is a bond or contains 1 to 4 carbon atoms and most favourably 1 to 2 carbon atoms. A particularly favourable group Z is xe2x80x94CH2xe2x80x94. In this instance, particularly suitable moieties NR11R12 include those wherein NR11R12 is amino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino. Most especially, xe2x80x94ZNR11R12, as a substituent on a heteroaromatic ring in the definition of R7, is preferably CH2N(CH3)2.
A further preferred class of compound of formula (I) is that wherein R7 represents halogen (especially iodine), hydroxy, vinyl, N3 or xe2x80x94OSO2Ra (especially where Ra is methyl).
Another preferred class of compound of formula (I) is that wherein R8 is hydrogen or methyl, and especially hydrogen.
A further preferred class of compound of formula (I) is that wherein n is 1 or 2, and especially wherein n is 1.
Another preferred class of compound of formula (I) is that wherein one of R9 and R10 is hydrogen, and especially wherein R9 and R10 are both hydrogen atoms.
One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof: 
wherein
A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
A4 is methyl or hydroxymethyl; and
R7 and n are as defined in relation to formula (I).
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms xe2x80x9cfluoroC1-6alkylxe2x80x9d and fluoroC1-6alkoxyxe2x80x9d means a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms Similarly, the term xe2x80x9cfluoroC1-4alkylxe2x80x9d means a C1-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
When used herein the term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Specific compounds within the scope of this invention include:
(2R,3S,4R,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-phenyl-4-vinyltetrahydropyran;
(2R,3R,4S,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-phenyl-4-vinyltetrahydropyran;
(2R,3S,4S,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-hydroxymethyl-3-phenyltetrahydropyran;
(2R,3S,4S,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(methanesulfonyloxy)methyl-3-phenyltetrahydropyran;
(2RS,3SR,4SR,8RS)-4-azidomethyl-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-oxy)-3-phenyltetrahydropyran;
(2RS,3SR,4SR,8RS)-4-aminomethyl-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)oxy)-3-phenyltetrahydropyran;
(2RS,3SR,4SR,8RS)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(dimethylamino)methyl-3-phenyltetrahydropyran;
(2RS,3SR,4SR,8RS)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(pyrrolidin-1-yl)methyl-3-phenyltetrahydropyran;
(2RS,3SR,4SR,8RS)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(1,2,4-triazol-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3S,4S,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-hydroxyethyl)-3-phenyltetrahydropyran;
(2R,3S,4R,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-methanesulfonyloxy)ethyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-hydroxymethyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-is(trifluoromethyl)phenyl)ethyl)oxy)-4-(methanesulfonyloxy)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-hydroxyethyl)-3-phenyltetrahydropyran;
(2R,3R,4S,8R)-2-(1-(1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-methanesulfonyloxy)ethyl-3-phenyltetrahydropyran;
and pharmaceutically acceptable salts thereof.
Further specific compounds of the present invention include:
(2R,3S,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-iodoethyl)-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(iodomethyl)-3-phenyltetrahydropyran;
(2R,3R,4S,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-iodoethyl)-3-phenyltetrahydropyran;
(2R,3S,4S,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-formyl-3-phenyltetrahydropyran;
(2R,3S,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(2-formylmethyl)-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-formyl-3-phenyltetrahydropyran;
(2R,3S,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-carboxymethyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-carboxy-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(4-methyl-4-carboxypiperidin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5,-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(4-ethoxycarbonylpiperidin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5,-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(4-carboxypiperidin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R,9(3xe2x80x2R))-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(3-ethoxycarbonyl-3-methylpiperldin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R,9(3xe2x80x2S))-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(3-ethoxycarbonyl-3-methylpiperidin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R,9(3xe2x80x2R))-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(3-carboxy-3-methylpiperidin-1-yl)methyl-3-phenyltetrahydropyran;
(2R,3R,4R,8R,9(3xe2x80x2S))-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(3-carboxy-3-methylpiperidin-1-yl)lmethyl-3-phenytetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-3-phenyl-4-(1,2,4-triazol-3-yl)methyltetrahydropyran;
(2R,3S,4S,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-3-phenyl-4-(1,2,4-triazol-3-yl)methyltetrahydropyran;
(2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-3-phenyl-4-(5-methoxycarbonyl-1,2,3-triazol-1-yl)ethyltetrahydropyran; (2R,3R,4R,8R)-2-(1-(1-(3,5-Bis(trifluoromethyl)phenyl)ethyl)oxy)-4-(4-methoxycarbonyl-1,2,3-triazol-1-yl)ethyl-3-phenyltetrahydropyran;
and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the xe2x80x9cparent drugxe2x80x9d or xe2x80x9cparent moleculexe2x80x9d) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I) and (Ia) will have the stereochemistry of the 2-, 3-, 4- and 8-positions as shown in formulae (Ib) and (Ic) 
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (Ia), formula (Ib) and formula (Ic).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer""s disease, senile dementia, dementia of the Alzheimer""s type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson""s disease, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson""s disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down""s syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn""s disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere""s disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud""s disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
Examples of such chemotherapeutic agents include alkylating agents, for example, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting, Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone or GABAB receptor agonists such as baclofen. Additionally, a compound of formula (I), either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron(trademark)) is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
Suitable methods for determining the anti-emetic effects of compounds of the present invention are well known in the art, for example, using the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6.
The compounds of formula (I) are also particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
The compounds of formula (I) are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I).
According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination. Thus, for example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a xcex22-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification Nos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-inflammatory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, xcex1-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HT1A receptor agonists or antagonists include, in particular, the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
The present invention accordingly provides the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptble salts thereof.
Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
The present invention accordingly provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an SSRI, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of formula (I) and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (I) and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of formula (I) and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
As used herein xe2x80x9cobesityxe2x80x9d refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich""s syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner""s syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
xe2x80x9cTreatmentxe2x80x9d (of obesity) refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
xe2x80x9cPreventionxe2x80x9d (of obesity) refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycyvstc ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
A further aspect of the present invention comprises the use of a compound of formula (I) for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of formula (I) for blocking the phase-shifting effects of light in a mammal.
The present invention further relates to the use of a compound of formula (I) for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal.
In a preferred embodiment, the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The present invention is further directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) (xe2x80x9cDIMSxe2x80x9d) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
As used herein the term xe2x80x9cmammalsxe2x80x9d includes animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
It will be appreciated that when using any combination described herein, both the compound of formula (I) and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term xe2x80x9ccombinationxe2x80x9d also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a xe2x80x9cfast dissolving oral formulationxe2x80x9d is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
By xe2x80x9creasonable period of timexe2x80x9d is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to a general process (A), compounds of formula (I), in which n is 1, may be prepared by the reaction of a compound of formula (II) 
wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); by reaction with an appropriate amine of the formula HNR11R12, or a heteroaromatic compound suitable for the addition of a five or six-membered nitrogen containing heteroaromatic ring as defined in relation to formula (I), or an azide such as sodium azide.
In each case, the reaction is preferably effected at an elevated temperature, for example, between 40xc2x0 C. and 80xc2x0 C., especially between 50xc2x0 C. and 60xc2x0 C. The reaction with a heteroaromatic compound is preferably effected in the presence of a suitable organic solvent such as dimethylformamide. The reaction with an azide is preferably effected in the presence of dimethylsulfoxide.
A particularly preferred compound of formula (II) is that wherein the group LG is mesylatexe2x80x94i.e. a compound of formula (I) in which R7 is the groupxe2x80x94OSO2CH3.
According to another general process (B), compounds of formula (I), in which R7 is hydroxy and n is 1 or 2, may be prepared by the interconversion of a corresponding compound of formula (I) in which n is zero and R7 is vinyl, hereinafter referred to as formula (III) 
by reaction with ozone, followed by a reaction with a reducing agent such as sodium borohydride (n is 1), or by reaction with a reducing agent such as borane.tetrahydrofuran complex, followed by hydrogen peroxide in the presence of a base such as sodium hydroxide.
According to another general process (C), compounds of formula (I) may be prepared by the reaction of a compound of formula (IV) with a compound of formula (V) 
preferably in the presence of a resin catalyst such as Amberlyst(trademark) 15, and 3 Angstrom molecular sieves.
The reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane, conveniently at room temperature.
According to another general process (D), compounds of formula (I), in which R6 is either methyl or hydroxymethyl, may be prepared by the reaction of a compound of formula (VI) 
wherein R7a is as defined for R7 in relation to formula (I) or, more preferably, is a precursor therefor; under either:
(a) (where R6 is methyl) catalytic hydrogenation conditions (e.g. H2, Pd(OH)2 on carbon) in a suitable solvent such as an ester, for example, ethyl acetate; or
(b) (where R6 is hydroxymethyl) reducing conditions (e.g borane or BH3.THF) followed by treatment with hydrogen peroxide and a base such as sodium hydroxide, conveniently in a solvent such as an ether, for example, tetrahydrofuran.
Where R7a is a precursor group (such as a TBDMS-protected hydroxyl group) deprotection is conveniently effected by treatment with an organic acid such as tetrabutylammonium fluoride.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (II) may be prepared by conventional methods from, for example, a corresponding compound of formula (I) in which R7 is a hydroxyl group. Thus, for example, when LG is a mesylate group a corresponding compound of formula (I) in which R7 is hydroxyl may be reacted with methanesulfonyl chloride in the presence of a base, such as triethylamine. The reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (III) may be prepared, for example, by the method of general process (C), above.
Compounds of formula (IV) may be prepared by the reduction of a compound of formula (VII) 
using conventional conditions such as sodium borohydride in the presence of a transition metal catalyst such as cerium chloride hexahydrate, in a solvent such as alcohol, for example, ethanol; or using DiBAL in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (VII) in which R7 is vinyl, R8 is hydrogen and n is 1 may be prepared from a compound of formula (VIII) 
by reaction with a vinyl Grignard reagent such as vinylMgBr, preferably in the presence of copper(I)iodide, and a suitable solvent such as an ether, for example, tetrahydrofuran. This reaction is effected at reduced temperature, for example, below xe2x88x9240xc2x0 C. and preferably at xe2x88x9278xc2x0 C.
Compounds of formula (VI) may be prepared by the reaction of a compound of formula (X) 
with dimethyltitanocene in a solvent such as toluene, pyridine or tetrahydrofuran, or a mixture thereof.
Compounds of formula (X) may be prepared by the reaction of a compound of formula (VII) with L-Selectride(trademark) (lithium tri-sec-butylborohydride) followed by treatment with a compound of formula (XI) 
wherein Hal is a halogen atom, preferably chlorine.
Compounds of formula (V), (VIII) and (XI) are either known compounds or may be prepared by methods analogous to those described herein.
It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the NK1 receptor of less than 100 nM on said test method.